Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a "Molecular Second Look".

OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this "molecular second look" with conventional cytology and histopathology-based findings. METHODS/MATERIALS: We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing. RESULTS: A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1-8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified. CONCLUSIONS: The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes.

Optimizing the management of stage II endometrial cancer: the role of radical hysterectomy and radiation.

OBJECTIVE: The optimal management of stage II endometrial cancer remains uncertain. We examined the role of radical hysterectomy and adjuvant radiotherapy for stage II endometrial cancer. STUDY DESIGN: The Surveillance, Epidemiology, and End Results database was used to identify 1577 women with stage II endometrioid type endometrial adenocarcinoma who underwent surgical staging. RESULTS: The cohort included 1198 women who underwent simple hysterectomy (76%) and 379 who underwent radical hysterectomy (24%). Radical hysterectomy had no effect on survival (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.61-1.23). Patients who did not receive radiation were 48% (HR, 1.48; 95% CI, 1.14-1.93) more likely to die than those who underwent adjuvant radiotherapy. The survival benefit from radiation was most pronounced in women who underwent radical hysterectomy. CONCLUSION: Adjuvant radiation improves survival. Although the routine performance of radical hysterectomy does not appear to be justified, patients with high-risk stage II tumors appear to benefit from combination therapy with radical hysterectomy and radiotherapy.

Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior.

OBJECTIVE: To compare the clinical behavior and outcome of uterine carcinosarcomas and grade 3 endometrioid carcinomas. METHODS: Data on patients with grade 3 endometrioid adenocarcinomas and uterine carcinosarcomas, from 1988 to 2004, was obtained from the Surveillance, Epidemiology, and End Results database. Mortality was analyzed using Cox proportional hazards models. Survival analysis was performed with the Kaplan-Meier method and log rank test. RESULTS: The cohort included 8,986 women with 5,024 (56%) grade 3 endometrioid carcinomas and 3,962 (44%) uterine carcinosarcomas. Women with uterine carcinosarcomas were older (aged 70 years compared with 66 years; P<.001) and more often nonwhite (23% compared with 15%; P<.001). These women presented with more advanced disease (stage III/IV 41% compared with 31%; P<.001). Multivariable analysis demonstrated that uterine carcinosarcoma histology, advanced age, nonwhite race, and advanced stage were independent predictors of poor survival. Cancer-specific mortality was 45% lower in women with grade 3 endometrioid carcinomas (hazard ratio 0.55; 95% confidence interval [CI] 0.5-0.6). The 5-year cancer-specific survival was lower for women with uterine carcinosarcoma for each disease stage. Survival for stage IC was 38% (95% CI 33-45%) for uterine carcinosarcoma compared with 68% (95% CI 63-73%) for grade 3 endometrioid carcinoma. For stage III, survival was 22% (95% CI 19-26%) for uterine carcinosarcoma compared with 45% (95% CI 41-49%) for grade 3 endometrioid carcinoma. CONCLUSION: Carcinosarcomas present at more advanced stage and have worse survival than grade 3 endometrioid carcinomas. Carcinosarcomas may represent a distinct biologic entity. LEVEL OF EVIDENCE: II.

The utility of preoperative endometrial sampling for the detection of uterine sarcomas.

OBJECTIVE: Uterine sarcomas are aggressive cancers, often not recognized prior to surgical exploration. The goal of this study was to determine the utility of endometrial sampling in detecting uterine sarcomas and to examine factors associated with diagnostic inaccuracy. METHODS: All uterine tumors identified at hysterectomy from 1990 to 2006 were reviewed. Included patients underwent preoperative endometrial sampling reviewed at our center. Pathologic data was documented through review of hospital records. Statistical analysis was performed using Chi square test. RESULTS: 938 patients were identified. Preoperative sampling was available for review in 730 (78%) subjects. Uterine sarcomas occurred in 142 patients; 72 (51%) underwent preoperative sampling. Overall, endometrial sampling identified an invasive tumor in 84% (600/713), and the correct histology in 79% (564/713). Among women with sarcomas, preoperative sampling suggested an invasive tumor in 86% (62/72) and predicted the correct histologic diagnosis in 64% (46/72). The rate of detection of an invasive cancer by preoperative sampling was not statistically different among sarcomas and epithelial tumors (86% vs. 84%, p=0.76). Preoperative sampling was significantly less reliable in predicting the correct histology for uterine sarcomas (64% vs. 81%, p<0.0001). Similar trends were seen when sarcoma patients were compared to low-grade and high-grade epithelial cancers. Both biopsy and curettage had similar accuracy in diagnosing sarcomas (p=0.84). CONCLUSIONS: Endometrial sampling has a significantly lower predictive value in diagnosing uterine sarcomas compared to epithelial uterine malignancies. Biopsy and curettage have similar accuracy. Novel diagnostic techniques are needed to accurately identify uterine sarcomas preoperatively.

The utility and cost effectiveness of preoperative computed tomography for patients with uterine malignancies.

OBJECTIVE: To determine the utility and cost effectiveness of preoperative computed tomography (CT) in detecting disease extent in patients with uterine carcinoma. METHODS: Medical records of 762 patients with uterine malignancies at hysterectomy from 1990-2006 were reviewed. Study inclusion required preoperative abdominal-pelvic CT scan. All CT findings were correlated with intraoperative and pathologic data. Statistical analysis was performed using Fisher's exact test. Cost analysis was based on Medicare fee schedules. RESULTS: 250 subjects (33%), who underwent preoperative CT, comprised the study cohort. CT suggested metastases in 22 (9%) cases and altered management in 7 (3%). Incidental findings were noted in 43 cases (17%), and altered management in 7 (3%). Among complex atypical hyperplasia (CAH) and grade 1 endometrioid cancers, CT suggested metastases in 9% and demonstrated other incidental findings in 21%; management was altered in just 4% of patients. Similarly, among grade 2/3 endometrioid tumors, CT suggested metastases in 7%, and incidental findings in 14%; management was altered in 4% of cases. For high-risk histologies, CT altered management in 11% of papillary serous and clear cell cases and in 13% of sarcomas. CT findings more often altered management in women with high-risk histologies than in those with endometrioid carcinomas (p=0.05). Expenditure of $17,622 for CT imaging is required to alter management of one patient. CONCLUSIONS: Preoperative CT is costly, and rarely alters management in patients with uterine neoplasms, particularly among endometrioid carcinomas. CT may be beneficial in patients with high-risk histologies and requires further study.

The role of radiation in improving survival for early-stage carcinosarcoma and leiomyosarcoma.

OBJECTIVE: We examined the effect of radiation on survival for early-stage uterine carcinosarcomas and leiomyosarcomas. STUDY DESIGN: The surveillance, epidemiology, and end results database was used to identify patients with stage I/II carcinosarcomas and leiomyosarcomas. Logistic regression and Cox models were developed to determine radiation use and survival. RESULTS: Among 1819 women with carcinosarcomas and 1088 women with leiomyosarcomas, radiation was administered to 667 of the patients (37%) with carcinosarcomas and to 235 of the patients (22%) with leiomyosarcomas. In a multivariate model, adjuvant radiation reduced the risk of death by 21% in women with carcinosarcomas (hazard ratio, 0.79; 95% CI, 0.7-0.9). Radiation reduced mortality rates in patients with carcinosarcomas who had not undergone node dissection but had only a marginal effect on survival in node-negative women. Adjuvant radiation had no effect on survival for early-stage leiomyosarcomas (hazard ratio, 1.1; 95% CI, 0.9-1.4). CONCLUSION: Adjuvant radiotherapy improves survival for select patients with early-stage carcinosarcomas but is of limited value for leiomyosarcomas.

Natural history of established low grade cervical intraepithelial (CIN 1) lesions.

UNLABELLED: THE AIM of the present study was to ascertain the natural history of cervical intraepithelial lesions 1 (CIN 1) and to develop recommendations to optimize follow-up. PATIENTS AND METHODS: Patients referred for colposcopy from January, 1996 to July, 2005 were reviewed. A prospectively maintained database was quarried for demographic, clinical, and pathologic data. RESULTS: The cohort included 1,001 patients with CIN 1. At 6 months, 330 patients (49%) regressed to normal, 305 (45%) had persistent low grade, while 45 (7%) progressed to high grade lesions. At 12 months, of those with negative pathology at 6 months, 200 (80%) remained negative, 42 (16%) demonstrated low grade and 9 (4%) progressed to high grade lesions. Of those with low grade lesions at 6 months, 131 (50%) regressed, 121 (46%) had persistent low grade, and 10 (4%) progressed to high grade lesions. CONCLUSION: Our data demonstrates a low rate of progression for CIN 1, suggesting it may be reasonable to prolong the screening interval in women with CIN 1.

Early metastatic spread after a complete response in locally advanced vulvar cancer treated with neoadjuvant chemoradiation: a case report.

BACKGROUND: Preoperative chemoradiation for advanced vulvar cancer reduces the tumor size and decreases morbidity from operative resection. CASE: A woman with locally advanced vulvar cancer had no evidence of metastatic disease at presentation. She displayed complete resolution of her vulvar and groin disease but developed early metastatic spread to the lungs and bone. CONCLUSION: Despite excellent local control, patients with locally advanced vulvar cancer are at risk for early metastatic spread. The effect of delayed surgical intervention, ifany, is unknown.

Vacuum-assisted closure in the treatment of complex gynecologic wound failures.

BACKGROUND: Complex wound failures are a source of significant morbidity and mortality. They are costly and time consuming to treat, and may evolve into chronic, debilitating conditions. Vacuum-assisted closure is a novel wound healing technique applying subatmospheric pressure to wounds to expedite healing. CASES: We report the successful use of vacuum-assisted closure therapy on three patients on a gynecologic oncology service with complex wound failures of various chronicity. In all cases, vacuum-assisted closure therapy was well tolerated and demonstrated efficacy within 48 hours of initiation. CONCLUSION: We conclude that vacuum-assisted closure therapy should be included in the armamentarium of the gynecologist addressing complex wound failures.

The incidence of port-site metastases in gynecologic cancers.

OBJECTIVES: To determine the incidence of port-site metastases in patients undergoing laparoscopic procedures for gynecologic cancers. METHODS: The charts of patients treated by laparoscopy for diagnosis, treatment, or staging of gynecologic cancers by the academic faculty attending physicians were studied from July 1, 1997 to June 30, 2001. No patient without a histological or cytological diagnosis of cancer from the index procedure were included. Fisher's exact test was used for statistical analysis. RESULTS: Eighty-three patients were identified accounting for 87 procedures. Types of cancer treated included endometrial (39), ovarian (29), and cervical (14). Twenty procedures were performed for recurrence of ovarian or peritoneal cancer, and ascites was present in 10 cases. Port-site metastases occurred in 2 patients accounting for 8 sites. Five sites were diagnosed in a single patient 13 days after a second-look laparoscopy for stage IIIB ovarian cancer, and 3 sites were diagnosed in a patient 46 days after an interval laparoscopy for stage IIIC primary peritoneal cancer. Ascites was present in both patients. The overall incidences of port-site metastases per procedure and per port placed were 2.3% (2/87) and 2.4% (8/330), respectively. In patients with a recurrence of ovarian or peritoneal cancer, no port-site metastases (0/16) occurred in the absence of ascites, whereas 50% (2/4) of patients with ascites developed port-site metastases (P < .035). CONCLUSIONS: The overall incidence of port-site metastases in gynecologic cancers in our study was 2.3%. The risk of port-site metastases is highest (5%) in patients with recurrence of ovarian or primary peritoneal malignancies undergoing procedures in the presence of ascites.

Racial disparities for uterine corpus tumors: changes in clinical characteristics and treatment over time.

BACKGROUND: Black women with endometrial cancer have been more likely to die than white patients. The authors examined factors associated with the poor outcome for black women with uterine corpus tumors and analyzed whether these characteristics have changed over time based on year of diagnosis. METHODS: The authors examined women with uterine neoplasms recorded from 1988-2004 in the Surveillance, Epidemiology and End Results (SEER) Database. The authors developed Cox proportional hazards models to examine the effect of race on survival and stratified women by year of diagnosis into 3 groups: 1988-1993, 1994-1998, 1999-2004. RESULTS: A total of 80,915 patients including 5564 (7%) black women were identified. Black patients were significantly younger, had more advanced stage tumors, and had more aggressive, nonendometrioid histologic variants (P<.001). Black women were 60% more likely to die from their tumors than white women when matched for other prognostic variables (hazards ratio, 1.60; 95% confidence interval, 1.51-1.69). For each of the 3 time periods, survival was worse for blacks even when stratified by stage and histology. Over time, the incidence of serous and clear-cell tumors increased, and the use of radiation decreased for both races. Staging lymphadenectomy was performed more commonly in both blacks (45%) and whites (48%) who had been treated more recently. CONCLUSIONS: Black women with uterine corpus tumors were more likely to die from their disease. This survival difference has persisted over time. The clinical characteristics of blacks and whites have remained relatively constant. The proportion of women who undergo surgical staging has increased with time and was well matched between races.

Improved survival for fallopian tube cancer: a comparison of clinical characteristics and outcome for primary fallopian tube and ovarian cancer.

BACKGROUND: Fallopian tube cancers are rare neoplasms. These malignancies are thought to behave biologically and clinically like ovarian cancer. The purpose of this study was to compare the clinical behavior and outcome of fallopian tube and ovarian cancer. METHODS: The Surveillance, Epidemiology, and End Results database was reviewed to identify women with tumors of the fallopian tube (FT) and ovary (OV) diagnosed between 1988 and 2004. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using Cox models and the Kaplan-Meier method. RESULTS: A total of 55,825 patients were identified, 1576 (3%) with FT and 54,249 (97%) with OV cancer. FT patients were more likely to present with early stage tumors (P < .001). Among FT patients, 47% had stage I/II tumors compared with 29% of OV cancers. In an adjusted Cox model of all patients, cancer-specific mortality was 48% lower in FT patients (hazard ratio, 0.52; 95% confidence interval [CI], 0.48-0.56) compared with OV cancer. Among patients with FT tumors, advanced age and stage were independent predictors of decreased survival. When stratified by stage, survival was similar for stage I and II tumors, but stage III and IV FT patients had an improved survival. The 5-year survival for stage III FT cancer was 54% (95% CI, 48%-60%), compared with 30% (95% CI, 29%-31%) for OV. CONCLUSIONS: Fallopian tube cancers present earlier and at advanced stage have a better overall survival than primary ovarian malignancies. Future clinical trials should recognize the possible distinct clinical behavior of fallopian tube cancers.

Laparoscopic lymphadenectomy for gynecologic malignancies using ultrasonically activated shears: analysis of first 100 cases.

OBJECTIVE: To evaluate the feasibility, safety and utility of the ultrasonic shears for laparoscopic pelvic and para-aortic lymph node retrieval in the treatment of gynecologic cancers. METHODS: Data on laparoscopic lymphadenectomy performed for gynecologic malignancies using ultrasonic shears over a 5-year period were collected and analyzed prospectively. RESULTS: Laparoscopic lymphadenectomy using ultrasonic shears was performed on 100 patients with a median age of 58 (17-87) years. The types of malignancies included cervical (n = 29), endometrial (n = 48), ovarian (n = 15), fallopian tube (n = 2), malignant mixed mesodermal tumor (n = 2), vaginal (n = 2) and synchronous ovarian and endometrial cancers (n = 2). Sites of lymphadenectomy included pelvic (n = 49), para-aortic (n = 30) or both pelvic and para-aortic (n = 21). The median nodal yield was 22 (0-87). 66/100 were complete lymphadenectomies with a median nodal yield of 28 (2-71). The median length of hospital stay was 2 (1-13) days and the average blood loss was 148 (0-500) ml. Overall complication rate was 13%. There were 3 intra-operative complications, which were all managed laparoscopically. There were no unplanned conversions to laparotomy. There were 10 post-operative complications including port-site metastasis in a patient with positive nodes (n = 1), trocar-site hernia requiring a second laparoscopy (n = 1), deep leg vein thrombosis (n = 1), and a small bowel obstruction (n = 1). CONCLUSIONS: This is the largest series to date demonstrating the safety and efficacy of ultrasonic shears in laparoscopic lymphadenectomy for gynecologic malignancies. In addition to the potential for lowering the risk for tissue damage, ultrasonic shears offer multifunctionality which allows for a simpler technique with the use of fewer instruments.

Ovarian mucinous cystadenocarcinoma with virilization.

BACKGROUND: Ovarian neoplasms, other than sex cord--stromal tumors, are rare causes of hyperandrogenism. Only two cases of primary mucinous carcinomas associated with virilization have been reported. CASE: A 50-year-old female was referred to our clinic with a large pelvic mass. On examination she had significant facial hirsutism, clitoromegaly, and male pattern pubic hair growth. Serum levels of testosterone and dihydroepiandrosterone sulfate were elevated. A 30-cm, multilocular, solid and cystic, left ovarian mass was resected. Histology revealed moderately to poorly differentiated mucinous cystadenocarcinoma. The ovarian stroma contained florid proliferation of luteinized cells. The right ovary showed cortical stromal hyperplasia. Abnormal hormone values normalized 10 days postoperatively. CONCLUSION: We report a rare case of mucinous cystadenocarcinoma with virilization, review the literature, and discuss the mechanisms of hormone production by these tumors.

Prophylactic oophorectomy: a morphologic and immunohistochemical study.

BACKGROUND: The tumorigenesis of ovarian carcinoma is poorly understood. The authors studied morphologic features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries, normal ovaries, and papillary serous ovarian carcinomas to identify possible preneoplastic changes in ovarian surface epithelium. METHODS: Morphologic features and immunohistochemical expression patterns of CA-125, Ki-67, p53, E-cadherin, and Bcl-2 were evaluated in 21 normal ovaries, 31 ovaries that were removed prophylactically for increased carcinoma risk, and 7 ovarian papillary serous carcinomas. Representative slides from formalin-fixed, paraffin-embedded tissue blocks were submitted to immunohistochemical staining and were evaluated independently by three gynecologic pathologists. For statistical analyses, Fisher exact tests, multivariate analyses, Spearman rank correlation coefficients, Wald statistics, Kruskal-Wallis tests, and Mann-Whitney tests were used. Immunohistochemical staining results were correlated with morphologic findings. RESULTS: The authors found progressive increases in reactivity with the lowest expression in normal ovarian epithelium, stronger expression in epithelium from prophylactically removed ovaries, and the highest expression in carcinomas for Ki-67 and p53. A similar trend was observed for CA-125. Positivity for Ki-67 and p53 was seen predominantly in the epithelium of inclusion cysts and deep invaginations, including those areas that had been identified as hyperplastic or dysplastic on routine hematoxylin and eosin-stained sections. CONCLUSIONS: The current results suggest biologic/molecular evidence for the existence of preneoplastic changes in ovarian surface epithelium and support the previously proposed concept of ovarian dysplasia. Subtle morphologic alterations of the ovarian epithelium may be biologically significant.

Immunohistochemical staining of GLUT1 in benign, borderline, and malignant ovarian epithelia.

BACKGROUND: Aberrant expression of the facilitative glucose transporter GLUT1 is found in a wide spectrum of epithelial malignancies. The authors describe an immunohistochemical study of GLUT1 expression in benign, borderline, and malignant ovarian epithelia. METHODS: One hundred forty one formalin-fixed, paraffin-embedded sections were immunostained with rabbit anti-GLUT1 using the streptavidin-biotin method. The samples were as follows: 3 endometriotic cysts, 9 serous cystadenomas, 15 mucinous cystadenomas, 17 noninvasive borderline implants, 3 invasive borderline implants, and 3 endosalpingiosis. In addition, 35 borderline tumors (26 serous, 7 mucinous, 2 seromucinous) and 56 adenocarcinomas (50 serous, 4 endometrioid, 2 mucinous) were stained. RESULTS: Benign serous and mucinous cystadenomas and endosalpingiosis were non-staining with GLUT1 antiserum. Twenty-eight of 35 borderline tumors (80%) stained positively, with weak to moderate (1-2+ out of 3) staining intensity and focal or patchy distribution. Seventeen noninvasive serous borderline implants were negatively stained; however, three invasive serous borderline implants were positively stained with GLUT1 antiserum. Fifty four of 56 ovarian carcinomas (96%) stained positively, with moderate to strong (2-3+ out of 3) intensity and multifocal distribution. CONCLUSIONS: GLUT1 is a consistent marker of ovarian epithelial malignancy. GLUT1 staining is absent in benign ovarian epithelial tumors, and shows progressively more staining in invasive tumors as compared to borderline tumors. Anti-GLUT1 antibody may be useful in distinguishing invasive from noninvasive serous borderline implants.

Caracterizaçäo morfométrica das lesöes do colo uterino relacionadas ao vírus da papilomatose humana / Morphometric characterization of cervix uteri lesions related to human papillomatosis virus

Este estudo é voltado para os seguintes aspectos ligados às lesSes cervicais relacionadas ao Vírus da Papilomatose Humana (VPH): 1) identificaçäo do vírus em tecido histologicamente normal; 2) diferenciaçäo morfométrica das alteraçSes induzidas pelo subtipo do VPH em condilomas, e 3) as diferenças morfométricas entre condiloma puro e Neoplasia Cervical Intraeptelial do Grau I (NIC I). Usamos o índice morfométrico núcleo/citoplasmático para as medidas da área, perímetro e máximo diâmetro, da célula e do núcleo celular. Quarenta e oito lâminas de biópsias cervicais foram estudadas e os achados, classificados dentro de três grupos: normal (22 casos), condiloma (20 casos) e NIC I (6 casos). A presença do DNA do VPH, detectada usando-se a metodologia da hibridizaçäo in situ, foi usada para estudar se o tecido histologicamente normal seria reconhecido como sendo infectado pelo VPH. Os casos de condiloma foram entäo comparados por meio de análise morfométrica para o subtipo do DNA do VPH por hibridizaçäo in situ, a fim de diferenciar os subtipos de VPH de baixo e alto risco. Os parâmetros foram avaliados por análise multivariada e demonstraram classificar corretamente todos os casos, exceto dois, com uma probabilidade posterior bastante elevada. Concluímos que os dados morfométricos foram úteis no diagnóstico diferencial entre as lesöes cervicais relacionadas ao VPH.